PROJECTSUMMARY: Chronicinfections,suchashumanimmunodeficiencyvirus,hepatitisCandBvirusesandcancers,including melanomaandnon-smallcelllungcancer,resultinwidespreadmorbidityandmortalityacrosstheglobe. Productiveimmuneresponsesarecriticalforthemaintenanceofhealthinpatientsafflictedwiththese diseases,yetchronicexposuretoantigenresultsinthefunctional?disarmament?ofrespondingTcells.This processistermed?exhaustion?andischaracterizedbythehierarchicallossofcytokineproduction,reductionin proliferativecapacityandconstitutiveexpressionofsurfaceinhibitoryreceptors.Overthepastdecade, significantprogresshasbeenmadeincharacterizingthetranscriptionfactors,inhibitoryreceptorsandsoluble mediatorsthatresultinthisprocess.Moreover,recentreportshavesuggestedthatchromatinaccessibilityand histonemodificationsmayplayasignificantroleinestablishingthisdysfunctionalphenotype.Yet,the molecularmechanismsthatinduceandregulateexhaustionarepoorlyunderstood.Therefore,inaneffortto guidethedevelopmentofnewandmoreeffectivetherapies,theprimarypurposeofthisproposalistoincrease ourunderstandingofthemechanismsthatinitiateandmaintainTcellexhaustionduringprotractedexposureto antigen. Utilizingcomputationalapproaches,wehaverecentlyidentifiedaparticularchromatin-associatedprotein,Tox, asapossiblekeyplayerinexhaustion.Amemberofthehigh-mobilitygroupproteins,Toxistheorizedtobindto DNA and modify local chromatin structure, resulting in significant changes in gene transcription. Though the proteinhasbeenshowntoplaycriticalrolesinthedevelopmentofNK,innate-likeandCD4Tcells,itsrolein regulatingperipheralresponsestoantigenareunexplored.Ourpreliminarydatashowsthatincontrasttoacute infection,whichresultsinthedownregulationofToxinperipheralTcells,chronicantigenexposureresultsina substantialincreaseintheexpressionofthisprotein.Thus,thethecentralhypothesizeofthisproposalis thatToxrespondstochronicantigenexposurebymodulatingthechromatinaccessibilityofregulatory regionsthatcontroltheexpressionoftranscriptionfactorsthatmediatethedysfunctionofexhaustion. Thestudiesdescribedwithinthisproposalarepoweredtoexplorethishypothesisandwillultimatelyelucidate theroleofToxingoverningdifferentialresponsestoacuteandchronicinfection.